Neuron

Introduction
p-Synephrine (Synephrine, Oxedrine) is a common ingredient in fat burning supplements and was made popular after the FDA's ban on ephedra. For the last 8-10 years, this compound was lambasted in the media for being dangerous and even deadly. A plethora of scientific reviews on synephrine were published in which the scientific community hysterically called for its banning due to case reports of strokes and heart attacks after individuals reported using synephrine-containing fat burners.

The reviews referenced older pharmacological studies on "synephrine" which pointed out its highly vasoconstrictive nature, and therefore its ability to induce arrhythmias, strokes, and heart attacks, were all the more likely. Unfortunately, the "synephrine" they were referencing was m-Synephrine, a popular OTC nasal decongestant also known as Phenylephrine (7).

m-Synephrine, in contrast to p-Synephrine, is not a natural alkaloid found in Citrus aurantium (Bitter Orange extract). The story becomes even more confusing because chemical analysis of synephrine-containing fat burners have indeed found m-Synephrine in addition to p-Synephrine (1). Whether or not these companies intentionally spiked their products, or if it was simply the result of poor quality control, the end result was almost the banning of a fairly benign compound. Luckily, a more detailed analysis of the constituents of C. aurantium has excluded m-Synephrine from its natural components.

To make matters more complicated, the natural alkaloid p-Synephrine exists only as (+)-p-Synephrine, whereas synthetically produced p-Synephrine exists as a 50/50 racemic mixture of (-)/(+)-p-Synephrine. The (-)-p-Synephrine enantiomer has no activity, and it is not presently known whether this form of p-Synephrine will antagonize the more active form. In fact, the body naturally converts the more active (+)-p-Synephrine to (-)-p-Synephrine as a method of deactivation.

Structure and Activity
p-Synephrine possesses a hydroxyl (-OH) group on the benzene ring. This substituent increases the polarity of the benzene ring which reduces blood brain barrier (BBB) penetration. Furthermore, it possesses a hydroxyl substituent on the beta carbon which also reduces BBB penetration (See Ephedrine vs. Amphetamine). The combination of both hydroxyls essentially precludes any CNS effects.

Similarly, a hydroxyl group in the para position is a metabolic stepping-stone towards complete elimination. For example, the main human metabolites of amphetamine are p-hydroxyamphetamine and p-hydroxynorephedrine. Para-hydroxylation also greatly enhances its interaction with Phase II metabolism, which partially explains its shorter half-life in comparison to similar non-phenolic isomers.

Finally, p-Synephrine possesses a secondary terminal-amine which generally tips the balance in favor of beta adrenergic affinity vs. alpha adrenergic affinity in comparison to its norsynephrine analogue, although studies have clearly shown that p-Synephrine is functionally inert at physiological concentrations (See Pharmacodynamics below).

Pharmacokinetics
The half-life of p-Synephrine is between 2 to 3 hours (3). Its main metabolites will be p-hydroxymandelicaldehyde via monoamine oxidase (MOA), and conjugated products via phase II metabolism. In the past, there was speculation in the literature that p-Synephrine could be converted to Octopamine en vivo, although human studies have revealed no conversion (4). Similarly, it is conceivable that p-Synephrine could be converted to epinephrine by microsomal hydroxylase enzymes in the liver, although there has not been any direct evidence of this actually occurring (5). An oral dose of 46.9 mg has been shown to reach a maximum blood concentration of 2 ng/mL in humans (3).

Pharmacodynamics
Despite being so closely similar in structure to m-Synephrine, p-Synephrine is exponentially weaker at agonizing adrenergic receptors. Studies have shown that p-Synephrine is essentially 50x less potent then m-Synephrine at agonizing the alpha-1 receptor (3). This is a very good characteristic since it decreases the amount of direct vasoconstriction the compound is able to achieve. Highly vasoconstrictive agents increase peripheral vascular resistence and can precipitate strokes, heart attacks, or generalized peripheral ischemia. Conversely, p-Synephrine is approximately 40,000 x less potent then norepinephrine at agonizing either the beta-1 or beta-2 receptor. The latter receptor is responsible for the vast majority of inducible lipolysis.

Vesicular Exchange-Diffusion
Similar to other compounds discussed previously (Tyramine, Octopamine, 1,3-DMAA), p-Synephrine likely participates in vesicular exchange-diffusion with endogenous catecholamines. This means that, upon supplementation, p-Synephrine is transported into neurons and becomes packaged into vesicles near the nerve terminal. This event displaces compounds like norepinephrine and epinephrine into the synapse where they can participate in adrenergic signaling. Acute supplementation of p-Synephrine in doses greater then 50 mg has demonstrated this effect in humans (6). Although the authors of the previously mentioned study attributed the cardiovascular effects of p-Synephrine to direct agonism, a more plausible mechanism is vesicular exchange diffusion as discussed above.

p-Synephrine and Fat Loss
As previously mentioned, the primary mechanism for fat loss in humans is by the extracellular agonism of beta-2 receptor on adipocytes. Nevertheless, a much smaller proportion can also be induced by the agonism of alpha-1, beta-1, and beta-3 receptors. Similarly, antagonizing alpha-2 receptors can potentiate the mechanism induced by beta-2 receptors. With that said, the literature is fairly clear that p-Synephrine has essentially no physiological agonism of any adrenergic receptor.

In a 2011 study in which they tested p-Synephrine against human adipocytes at concentrations of up to 10,000 ng/mL, no lipolysis was observed (8). To put this into the proper context,  taking ~50 mg of p-Synephrine by mouth results in a maximum blood concentration of 2 ng/mL. Obviously, 10,000 ng/mL is not achievable by oral supplementation of any amount, and so p-Synephrine can be ruled-out as a direct facilitator of fat loss.

Conversely, it is plausible that p-Synephrine can enhance fat loss in other ways. For example, a Citrus aurantium extract was demonstrated to increase the thermic effect of food in women, but not men (9). Another study, published in 2011, measured the resting metabolic rate (RMR) of synephrine alone, or in combination with the bioflavonoids naringin, and hesperidin.

The fourth condition which combined Advantra Z (50 mg p-Synephrine), hesperidin 100 mg, and naringin 600 mg, resulted in a RMR increase of approximately 17.7 % in comparison to placebo (10). To put this into context, the combination of 70 mg caffeine and 24 mg ephedrine has been demonstrated to increase RMR 8% in comparison to placebo (11). The explanation for the increase in RMR in this p-Synephrine study is currently unknown, although it is possible that the bioflavonoids competitively inhibited Phase II metabolism to some degree, and thereby increased the amount of p-Synephrine reaching the blood stream. Whether or not these transient elevations in RMR actually translate into physiological consequence remains to be seen. It should also be noted that the makers of Advantra Z funded the study, and so bias should be entertained.

Summary
p-Synephrine is an extracted alkaloid from Bitter orange that is commonly seen in fat loss formulas. Its popularity soared as a replacement for Ma Haung ephedra after 2004, and its history has been marked for being mistaken for m-Synephrine. Presently, only one placebo-controlled trial has been published which has examined Citrus aurantium/p-Synephrine for the end-point of weight loss (12). No clinical significance was seen.

 

Neuron

Introduction
p-Synephrine (Synephrine, Oxedrine) is a common ingredient in fat burning supplements and was made popular after the FDA's ban on ephedra. For the last 8-10 years, this compound was lambasted in the media for being dangerous and even deadly. A plethora of scientific reviews on synephrine were published in which the scientific community hysterically called for its banning due to case reports of strokes and heart attacks after individuals reported using synephrine-containing fat burners.

The reviews referenced older pharmacological studies on "synephrine" which pointed out its highly vasoconstrictive nature, and therefore its ability to induce arrhythmias, strokes, and heart attacks, were all the more likely. Unfortunately, the "synephrine" they were referencing was m-Synephrine, a popular OTC nasal decongestant also known as Phenylephrine (7).

m-Synephrine, in contrast to p-Synephrine, is not a natural alkaloid found in Citrus aurantium (Bitter Orange extract). The story becomes even more confusing because chemical analysis of synephrine-containing fat burners have indeed found m-Synephrine in addition to p-Synephrine (1). Whether or not these companies intentionally spiked their products, or if it was simply the result of poor quality control, the end result was almost the banning of a fairly benign compound. Luckily, a more detailed analysis of the constituents of C. aurantium has excluded m-Synephrine from its natural components.

To make matters more complicated, the natural alkaloid p-Synephrine exists only as (+)-p-Synephrine, whereas synthetically produced p-Synephrine exists as a 50/50 racemic mixture of (-)/(+)-p-Synephrine. The (-)-p-Synephrine enantiomer has no activity, and it is not presently known whether this form of p-Synephrine will antagonize the more active form. In fact, the body naturally converts the more active (+)-p-Synephrine to (-)-p-Synephrine as a method of deactivation.

Structure and Activity
p-Synephrine possesses a hydroxyl (-OH) group on the benzene ring. This substituent increases the polarity of the benzene ring which reduces blood brain barrier (BBB) penetration. Furthermore, it possesses a hydroxyl substituent on the beta carbon which also reduces BBB penetration (See Ephedrine vs. Amphetamine). The combination of both hydroxyls essentially precludes any CNS effects.

Similarly, a hydroxyl group in the para position is a metabolic stepping-stone towards complete elimination. For example, the main human metabolites of amphetamine are p-hydroxyamphetamine and p-hydroxynorephedrine. Para-hydroxylation also greatly enhances its interaction with Phase II metabolism, which partially explains its shorter half-life in comparison to similar non-phenolic isomers.

Finally, p-Synephrine possesses a secondary terminal-amine which generally tips the balance in favor of beta adrenergic affinity vs. alpha adrenergic affinity in comparison to its norsynephrine analogue, although studies have clearly shown that p-Synephrine is functionally inert at physiological concentrations (See Pharmacodynamics below).

Pharmacokinetics
The half-life of p-Synephrine is between 2 to 3 hours (3). Its main metabolites will be p-hydroxymandelicaldehyde via monoamine oxidase (MOA), and conjugated products via phase II metabolism. In the past, there was speculation in the literature that p-Synephrine could be converted to Octopamine en vivo, although human studies have revealed no conversion (4). Similarly, it is conceivable that p-Synephrine could be converted to epinephrine by microsomal hydroxylase enzymes in the liver, although there has not been any direct evidence of this actually occurring (5). An oral dose of 46.9 mg has been shown to reach a maximum blood concentration of 2 ng/mL in humans (3).

Pharmacodynamics
Despite being so closely similar in structure to m-Synephrine, p-Synephrine is exponentially weaker at agonizing adrenergic receptors. Studies have shown that p-Synephrine is essentially 50x less potent then m-Synephrine at agonizing the alpha-1 receptor (3). This is a very good characteristic since it decreases the amount of direct vasoconstriction the compound is able to achieve. Highly vasoconstrictive agents increase peripheral vascular resistence and can precipitate strokes, heart attacks, or generalized peripheral ischemia. Conversely, p-Synephrine is approximately 40,000 x less potent then norepinephrine at agonizing either the beta-1 or beta-2 receptor. The latter receptor is responsible for the vast majority of inducible lipolysis.

Vesicular Exchange-Diffusion
Similar to other compounds discussed previously (Tyramine, Octopamine, 1,3-DMAA), p-Synephrine likely participates in vesicular exchange-diffusion with endogenous catecholamines. This means that, upon supplementation, p-Synephrine is transported into neurons and becomes packaged into vesicles near the nerve terminal. This event displaces compounds like norepinephrine and epinephrine into the synapse where they can participate in adrenergic signaling. Acute supplementation of p-Synephrine in doses greater then 50 mg has demonstrated this effect in humans (6). Although the authors of the previously mentioned study attributed the cardiovascular effects of p-Synephrine to direct agonism, a more plausible mechanism is vesicular exchange diffusion as discussed above.

p-Synephrine and Fat Loss
As previously mentioned, the primary mechanism for fat loss in humans is by the extracellular agonism of beta-2 receptor on adipocytes. Nevertheless, a much smaller proportion can also be induced by the agonism of alpha-1, beta-1, and beta-3 receptors. Similarly, antagonizing alpha-2 receptors can potentiate the mechanism induced by beta-2 receptors. With that said, the literature is fairly clear that p-Synephrine has essentially no physiological agonism of any adrenergic receptor.

In a 2011 study in which they tested p-Synephrine against human adipocytes at concentrations of up to 10,000 ng/mL, no lipolysis was observed (8). To put this into the proper context,  taking ~50 mg of p-Synephrine by mouth results in a maximum blood concentration of 2 ng/mL. Obviously, 10,000 ng/mL is not achievable by oral supplementation of any amount, and so p-Synephrine can be ruled-out as a direct facilitator of fat loss.

Conversely, it is plausible that p-Synephrine can enhance fat loss in other ways. For example, a Citrus aurantium extract was demonstrated to increase the thermic effect of food in women, but not men (9). Another study, published in 2011, measured the resting metabolic rate (RMR) of synephrine alone, or in combination with the bioflavonoids naringin, and hesperidin.

The fourth condition which combined Advantra Z (50 mg p-Synephrine), hesperidin 100 mg, and naringin 600 mg, resulted in a RMR increase of approximately 17.7 % in comparison to placebo (10). To put this into context, the combination of 70 mg caffeine and 24 mg ephedrine has been demonstrated to increase RMR 8% in comparison to placebo (11). The explanation for the increase in RMR in this p-Synephrine study is currently unknown, although it is possible that the bioflavonoids competitively inhibited Phase II metabolism to some degree, and thereby increased the amount of p-Synephrine reaching the blood stream. Whether or not these transient elevations in RMR actually translate into physiological consequence remains to be seen. It should also be noted that the makers of Advantra Z funded the study, and so bias should be entertained.

Summary
p-Synephrine is an extracted alkaloid from Bitter orange that is commonly seen in fat loss formulas. Its popularity soared as a replacement for Ma Haung ephedra after 2004, and its history has been marked for being mistaken for m-Synephrine. Presently, only one placebo-controlled trial has been published which has examined Citrus aurantium/p-Synephrine for the end-point of weight loss (12). No clinical significance was seen.

 

Neuron

Introduction
p-Synephrine (Synephrine, Oxedrine) is a common ingredient in fat burning supplements and was made popular after the FDA's ban on ephedra. For the last 8-10 years, this compound was lambasted in the media for being dangerous and even deadly. A plethora of scientific reviews on synephrine were published in which the scientific community hysterically called for its banning due to case reports of strokes and heart attacks after individuals reported using synephrine-containing fat burners.

The reviews referenced older pharmacological studies on "synephrine" which pointed out its highly vasoconstrictive nature, and therefore its ability to induce arrhythmias, strokes, and heart attacks, were all the more likely. Unfortunately, the "synephrine" they were referencing was m-Synephrine, a popular OTC nasal decongestant also known as Phenylephrine (7).

m-Synephrine, in contrast to p-Synephrine, is not a natural alkaloid found in Citrus aurantium (Bitter Orange extract). The story becomes even more confusing because chemical analysis of synephrine-containing fat burners have indeed found m-Synephrine in addition to p-Synephrine (1). Whether or not these companies intentionally spiked their products, or if it was simply the result of poor quality control, the end result was almost the banning of a fairly benign compound. Luckily, a more detailed analysis of the constituents of C. aurantium has excluded m-Synephrine from its natural components.

To make matters more complicated, the natural alkaloid p-Synephrine exists only as (+)-p-Synephrine, whereas synthetically produced p-Synephrine exists as a 50/50 racemic mixture of (-)/(+)-p-Synephrine. The (-)-p-Synephrine enantiomer has no activity, and it is not presently known whether this form of p-Synephrine will antagonize the more active form. In fact, the body naturally converts the more active (+)-p-Synephrine to (-)-p-Synephrine as a method of deactivation.

Structure and Activity
p-Synephrine possesses a hydroxyl (-OH) group on the benzene ring. This substituent increases the polarity of the benzene ring which reduces blood brain barrier (BBB) penetration. Furthermore, it possesses a hydroxyl substituent on the beta carbon which also reduces BBB penetration (See Ephedrine vs. Amphetamine). The combination of both hydroxyls essentially precludes any CNS effects.

Similarly, a hydroxyl group in the para position is a metabolic stepping-stone towards complete elimination. For example, the main human metabolites of amphetamine are p-hydroxyamphetamine and p-hydroxynorephedrine. Para-hydroxylation also greatly enhances its interaction with Phase II metabolism, which partially explains its shorter half-life in comparison to similar non-phenolic isomers.

Finally, p-Synephrine possesses a secondary terminal-amine which generally tips the balance in favor of beta adrenergic affinity vs. alpha adrenergic affinity in comparison to its norsynephrine analogue, although studies have clearly shown that p-Synephrine is functionally inert at physiological concentrations (See Pharmacodynamics below).

Pharmacokinetics
The half-life of p-Synephrine is between 2 to 3 hours (3). Its main metabolites will be p-hydroxymandelicaldehyde via monoamine oxidase (MOA), and conjugated products via phase II metabolism. In the past, there was speculation in the literature that p-Synephrine could be converted to Octopamine en vivo, although human studies have revealed no conversion (4). Similarly, it is conceivable that p-Synephrine could be converted to epinephrine by microsomal hydroxylase enzymes in the liver, although there has not been any direct evidence of this actually occurring (5). An oral dose of 46.9 mg has been shown to reach a maximum blood concentration of 2 ng/mL in humans (3).

Pharmacodynamics
Despite being so closely similar in structure to m-Synephrine, p-Synephrine is exponentially weaker at agonizing adrenergic receptors. Studies have shown that p-Synephrine is essentially 50x less potent then m-Synephrine at agonizing the alpha-1 receptor (3). This is a very good characteristic since it decreases the amount of direct vasoconstriction the compound is able to achieve. Highly vasoconstrictive agents increase peripheral vascular resistence and can precipitate strokes, heart attacks, or generalized peripheral ischemia. Conversely, p-Synephrine is approximately 40,000 x less potent then norepinephrine at agonizing either the beta-1 or beta-2 receptor. The latter receptor is responsible for the vast majority of inducible lipolysis.

Vesicular Exchange-Diffusion
Similar to other compounds discussed previously (Tyramine, Octopamine, 1,3-DMAA), p-Synephrine likely participates in vesicular exchange-diffusion with endogenous catecholamines. This means that, upon supplementation, p-Synephrine is transported into neurons and becomes packaged into vesicles near the nerve terminal. This event displaces compounds like norepinephrine and epinephrine into the synapse where they can participate in adrenergic signaling. Acute supplementation of p-Synephrine in doses greater then 50 mg has demonstrated this effect in humans (6). Although the authors of the previously mentioned study attributed the cardiovascular effects of p-Synephrine to direct agonism, a more plausible mechanism is vesicular exchange diffusion as discussed above.

p-Synephrine and Fat Loss
As previously mentioned, the primary mechanism for fat loss in humans is by the extracellular agonism of beta-2 receptor on adipocytes. Nevertheless, a much smaller proportion can also be induced by the agonism of alpha-1, beta-1, and beta-3 receptors. Similarly, antagonizing alpha-2 receptors can potentiate the mechanism induced by beta-2 receptors. With that said, the literature is fairly clear that p-Synephrine has essentially no physiological agonism of any adrenergic receptor.

In a 2011 study in which they tested p-Synephrine against human adipocytes at concentrations of up to 10,000 ng/mL, no lipolysis was observed (8). To put this into the proper context,  taking ~50 mg of p-Synephrine by mouth results in a maximum blood concentration of 2 ng/mL. Obviously, 10,000 ng/mL is not achievable by oral supplementation of any amount, and so p-Synephrine can be ruled-out as a direct facilitator of fat loss.

Conversely, it is plausible that p-Synephrine can enhance fat loss in other ways. For example, a Citrus aurantium extract was demonstrated to increase the thermic effect of food in women, but not men (9). Another study, published in 2011, measured the resting metabolic rate (RMR) of synephrine alone, or in combination with the bioflavonoids naringin, and hesperidin.

The fourth condition which combined Advantra Z (50 mg p-Synephrine), hesperidin 100 mg, and naringin 600 mg, resulted in a RMR increase of approximately 17.7 % in comparison to placebo (10). To put this into context, the combination of 70 mg caffeine and 24 mg ephedrine has been demonstrated to increase RMR 8% in comparison to placebo (11). The explanation for the increase in RMR in this p-Synephrine study is currently unknown, although it is possible that the bioflavonoids competitively inhibited Phase II metabolism to some degree, and thereby increased the amount of p-Synephrine reaching the blood stream. Whether or not these transient elevations in RMR actually translate into physiological consequence remains to be seen. It should also be noted that the makers of Advantra Z funded the study, and so bias should be entertained.

Summary
p-Synephrine is an extracted alkaloid from Bitter orange that is commonly seen in fat loss formulas. Its popularity soared as a replacement for Ma Haung ephedra after 2004, and its history has been marked for being mistaken for m-Synephrine. Presently, only one placebo-controlled trial has been published which has examined Citrus aurantium/p-Synephrine for the end-point of weight loss (12). No clinical significance was seen.

 

No Hype-

Just trying to get a better understanding of the possible long-term risks that may accompany their use.

In Alzheimer's disease, it is proposed that elevated background concentrations of glutamate between the pre and postsynaptic neurons causes the postsynaptic membrane to become more frequently depolarized, thus resulting in the displacment of the voltage-dependent Mg2+ ion that normally blocks the NMDA ion channel, followed by excitotoxic Ca2+ influx. This in turn negatively impairs physiological signaling mechanisms/synaptic plasticity/learning/memory ect.

The literature indicates that postsynaptic glutamate transporters remove glutamate from the synaptic cleft in a rapid fashion under normal physiological conditions. However, my concern is that NMDA supplementation [may] alter glutamate transport homeostasis, resulting in the inadequate removal of glutamate from the synaptic cleft, as a result of prolonged supraphysiological exposure to glutamate.

Now the implication from other respected members was that the voltage-gated NMDAR requires previous activation of the AMPA receptor for membrane depolarization. However if that's the case, I'd like to hear some discussion on the following....

"Originally Posted by Espinosa et al, 2009 "

"we propose that the residual NMDA receptor component of spontaneous mEPSCs stems from continual incomplete Mg2+
block of NMDA receptors at the resting membrane potential rather than unblock triggered by concurrent AMPA receptor activity."

"partial blockade of AMPA receptors does not affect the NMDA receptor-mediated component of mEPSCs arguing against the possibility that the NMDA component is due to relief of Mg2+ block via local depolarization mediated by AMPA receptors."

"These findings are consistent with our observations, and they strongly suggest that NMDA receptors are active at rest during spontaneous neurotransmission, despite their reduced ion conductance due to Mg2+ block."

"These findings indicate that mEPSC driven signaling is more widespread than previously thought and reinforce the premise that mEPSCs can drive biochemical signaling in addition to electrical activity."

"spontaneous glutamate release may constitute a bone fide pathway for interneuronal signaling independent of pre and postsynaptic activity."

Additionally, it has been suggested that NMDARs must bind to glutamate and to glycine prior to activation however, according to Papouin et al, 2012, D-serine displays preferential affinity for [synaptic] NMDARs, whereas glycine's affinity is [extrasynaptic]. The authors notate that excitotoxicity & LTP are exclusively governed by the coagonist D-serine in synaptic NMDARs.

Neuron-

"The NMDA receptor is a voltage-gated channel which requires previous activation of the AMPA receptor for membrane depolarization

since the compound "NMDA" cannot agonize the AMPA receptor, its ability to activate the NMDA receptor would be limited, and so a direct neurotoxic effect will not likely occur from oral supplementation

if you take a neuron in a vacuum (en vitro), its normal electrical homeostasis is disrupted, and the NMDA receptor no longer is voltage gated. if you bath this neuron in NMDA, excitotoxicity will occur, whereas en vivo it can't"

Cyrus-

"The bottom line is that we don't know what dose of oral NMDA can cause excitoxicity. Oral doses are far safer than injections into the brain because one of the primary functions of the BBB is to prevent excitoxic insult. I do not know how much NMDA penetrates the BBB per mg taken orally, but I do know that it will be less than an equivalent amount of DAA due to the active transport of AAs at the barrier. Assuming some methylation of DAA and conversion to NMDA in the brain (mediated endogenously of course), it's likely that the dose of NMDA provided by intimidate will be met through basic DAA supplementation (this assumes a 1% conversion rate). So, in my opinion, excitotoxicity is unlikely with intimidate.(NMDA product)"

Magnetotropic-

"This is a study of miniature excitatory postsynaptic currents (mEPSCs), not evoked EPSCs. The former is due to random release of unprovoked pre-synaptic neurotransmitter release, and the latter is due to the classical action potential induced sequence.

What this study says is that magnesium isn't permanently docked on the NMDAr, and that their may be times where the NMDA receptor is activated when magnesium is displaced. This is fairly obvious since the intracellular/extracellular polarity is not completely electrically static.

And since the AMPA receptor has its utilitiy in depolarizing the intracellular compartment allowing magnesium displacement, and thereby NMDA activation, if magensium is not docked on the NMDA receptor in the first place, then AMPA has lost its function (extremely temporarily).

AMPA receptor pre-activation is still required for the vast majority of glutaminergic NMDA signaling, and so the significance of this study is unknown.

It is worth noting that the article mentioned this:
 

Ultimately, I would say this study is interesting, but certainly does not alter the classical paradigm in any way.

Here is the authors final thoughts. Keep in mind that the context is key:

Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity."

The prevailing conception [at least within a community that utilizes supplemental NMDA] is that it poses no risk, as the NMDAR is voltage-gated, and that due to the fact that NMDA does not directly agonize the AMPA receptor, there is no forseeable risk to it's supplementation. Now this may, or may not be the case however, discussions like these reguarding theoretical implications on the subject are beneficial for educational purposes, at least to some degree.

So following the creation of this thread, we've established the fact that the NMDA compound does [not] have to directly agonize the AMPA receptor for postsynaptic depolarization to take place. Additionally, it appears as though both spontaneous and evoked neurotransmission can activate certain sets of NMDA and/or AMPA receptors.

Astrocytic PAR1-triggered glutamate efflux [may] be another mechanism by which depolarization relieves the Mg+2 block to potentiate NMDA receptor-mediated excitatory postsynaptic currents, however addmittedely, I haven't done much research on the subject.

Nonetheless, these factors at least open the possibility of excitotoxic insult - be it low risk or not.

--"These results support the notion that spontaneous and evoked neurotransmission activate distinct sets of AMPA receptors and bolster the hypothesis that synapses harbor separate microdomains of evoked and spontaneous signaling." - Yildirim et al, 2011

"Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side." - Deniz Atasoy et al, 2008

--Andy-

"Sustained, pathologically excessive Ca2+ influx is necessary for an apoptotic/necrotic cascade, and that requires a glutamate dump. If anything, calcium transients as a result of excess NMDA in the synapse would end up being beneficial, depending on the region and type of neuron, in new memory formation."

--So if the Ca2+ influx is transient, it won't likely be pathologically deleterious, even with prolonged use."

Andy-

"That's the physiologically sound consideration, yes.

Also regarding aggression, there's significant reason to believe LH and FSH can contribute to behavioral effects. I've been thinking about this for a long time because testosterone administration alone does not induce behavioral effects but anecdotal evidence abounds for some natural testosterone boosters, and it's been going on for too long for me to believe it's purely psychosomatic in every case."

Condescending Guy Dumbs It Down-

"Specific conditions must be met in order for NMDA activation (Mg2+ displacement)/excitotoxicity to occur, i.e. presynaptic NMDAR glutamate binding, and depolarization (which occurs with AMPAR glutamate binding, and an influx of Na+).

NO HYPE is questioning if NMDA activation/Mg2+ displacement can occur through alternative means, such as mEPSCs, or astrocytic PAR1-triggered glutamate efflux.

tms;du (too much science, didn't understand) Certain conditions must be met in order for excitotoxicity to occur, NO HYPE is questioning whether such toxicity may occur by other means."

Studies-

1.)

https://www.ncbi.nlm.nih.gov/pubmed/19261712

Under physiological conditions N-methyl-D-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg(2+). Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately -67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises approximately 20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately -50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

2.)

"Neuroprotective effects of creatine administration against NMDA and malonate toxicity.

Malcon C, Kaddurah-Daouk R, Beal MF.
Source

Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

We examined whether creatine administration could exert neuroprotective effects against excitotoxicity mediated by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Oral administration of 1% creatine significantly attenuated striatal excitotoxic lesions produced by NMDA, but had no effect on lesions produced by AMPA or kainic acid. Both creatine and nicotinamide can exert significant protective effects against malonate-induced striatal lesions. We, therefore, examined whether nicotinamide could exert additive neuroprotective effects with creatine against malonate-induced lesions. Nicotinamide with creatine produced significantly better neuroprotection than creatine alone against malonate-induced lesions. Creatine can, therefore, produce significant neuroprotective effects against NMDA mediated excitotoxic lesions in vivo and the combination of nicotinamide with creatine exerts additive neuroprotective effects."

Current studies show that there is enough transport enzymes available (and such an abundance of Histidine) that its not likely that there is even a considerable need for concern of depleting your taurine levels.

____________________________________________

https://suppversity.blogspot.com/2011...omyocytes.html
Beta Alanine Suffocates Cardiomyocytes, Taurine Lets Them Breath Again: Taurine Regulates Mitochondrial Protein Synthesis and Protects Mitochondria Against Superoxide Generation.

 

Image 1: Beta alanine and taurine; the former interferes with uptake and reactions that involve the latter.

Having listened to the last installment of the Amino Acids for Super Humans series you are already familiar with the antagonism of the two beta-amino acids ("beta-" indicates that those are not part of the 22 proteinogenic amino acids) beta alanine and taurine. Being structurally very similar, both share a single transporter, so that high levels of beta alanine decrease/inhibit taurine uptake.

Like a partial agonist, beta alanine also interferes with the actions of taurine by inhibiting reactions that involve the former, so that the cardiomyocytes Jong and his colleagues from the Universities of South Alabama, USA, and Kobe, Japan, incubated with 5mM beta alanine for 48h induced a 45% decrease in taurine content in the neonatal rat cardiomyocytes. The sudden lack of taurine "enhanced superoxide generation, the inactivation of the oxidant sensitive enzyme, aconitase, and the oxidation of glutathione" (Jong. 2011), or, put simply, induced mitochondrial oxidative stress.

Associated with the increase in oxidative stress was a decline in electron transport activity, with the
activities of respiratory chain complexes I and III declining 50–65% and oxygen consumption falling 30%.
The decline in the activity of ND5 and ND6 respiratory chain complex subunits produced a "bottleneck" effect. Its almost as if you were trying to breath through a mask with two automated, taurine-powered openings. If you run out of "fuel", the valves in the openings won't open completely, you will gasping for air and (I bet) will become severely stressed.

Figure 1: Oxygen consumption [in % of baseline] in control and in cardiomyocytes incubated with 5mM beta alanine. (data adapted from Jong. 2011)

Before you do now flush all your beta alanine and beta alanine containing products down the toilette, consider this: The existing data on the safety of beta alanine makes it quite clear that taken in individual (even large doses) your body is well able to avoid that the supplemental beta alanine "floods" your heart muscles, depletes their taurine stores and suffocates their mitochondria. How so? Well, firstly it can distribute the beta alanine over millions of brain and muscle cells (something that obviously could not happen in the petri-dish with isolated cardiomyocytes the scientists used in this experiment), where it will ideally bind to histidine and form the potent intracellular buffer and anti-oxidant carnosine. And secondly, your body can mimic Jong, Azuma & Schaffer, who added 5mM of taurine to the solution. Now, with one molecule of taurine "buffering" each of the beta alanine molecules, the negative effects of beta alanine on the electron transport chain were blocked.

As I have emphasized before, observations like these should make you reconsider the usefulness of isolated nutrient supplementation. Our understanding of the complex regulatory mechanisms and interaction that are taking place in our bodies are still very limited. Especially long term (or high dose) effects of many "supplements" (including amino acids, vitamins, fatty acids, herbs, etc.) have not been thoroughly investigated for many of the commercially available and, as it is the case with beta alanine, scientifically backed ergogenics, nootropics, fat burners etc. Oftentimes, looking at the nutrient-complex nature has wisely attached to what we ignorantly isolated and put into a tablet or powder, would suffice to know that, an amino acid like beta alanine, which occurs naturally in relatively low doses in slowly absorbed whole foods, mostly meat products, which obviously also contain taurine, was probably not meant to be ingested at high doses in isolated powder form. Co-ingestion (not necessarily at the same time) of adequate amounts of taurine or its precursors, methionine, respectively cysteine, would thus be the imperative prerequisite to benefit from the proven ergogenic effects (esp. during high-intensity exercise) of beta alanine.

Negatives:

Protein synthesis suppression

"Polyamines have been demonstrated to play an important role in the transformation process. Conversely, polyamine depletion results in growth arrest" (9, 10).

"Polyamines are required components for both protein and nucleic acid synthesis"

"Herein we report concurrent suppression of both polyamine biosynthesis and transport by agmatine."

https://www.jbc.org/cgi/content/full/273/25/15313

"Agmatine is absorbed from the gastrointestinal tract, probably by means of a specific transporter. It is likely that agmatine in the chyme of the gut represents an essential source of agmatine in the tissues of the organism. An increase in the availability of gastrointestinal agmatine for absorption impairs liver regeneration and may contribute to the development of liver diseases."
 

https://www.annalsnyas.org/cgi/content/abstract/1009/1/44

It would probably be a good idea to leave agmatine out of the NO products, since it's an endogenous, competitive inhibitor of NOS.[/B] :D

https://www.biochemj.org/bj/316/0247/3160247.pdf

POLYAMINE DEPLETION -
NEGATIVE EFFECTS ON PROTEIN SYNTHESIS AND CELL GROWTH :

"When inhibitors of polyamine biosynthesis are present and polyamine levels are low, [B]the rates of protein and nucleic acid synthesis are diminished[/B] [14,15], fidelity of translation is impaired [16] and chromosome disintegration may occur [17,21]."

"Polyamines are essential, low-molecular-weight organic cations that have been implicated in the biosynthesis of nucleic acids and proteins (25)." "Polyamine depletion also decreases general protein synthesis [5,38]."

[5] - Marton, L. J. and Morris, D. R. (1987) in Inhibition of Polyamine Metabolism

[14] - Whitney, P.A. and Morris, D.R. (1978) J. Bacteriol. 134, 214-220  

[15] - Jain, A. and Tyagi, A.K. (1987) Moll. Cell. Biochem. 78, 3-8

[16] - Koza R.A. and Herbst, E. (1992) Biochem. J. 281, 87-93

[17] - Knutila, S. and Pohjanpeto, P. (1983) Exp. Cell Res. 145, 222-226

[21] - Palvimo, J., Pojanpeto, P., Kankkurer, A.L. and Maenp, P.H. (1987) Biochim. Biophys. Acta 90, 21-29

[38] - Heby, O. (1981) Differentiation 19, 1?20

PHYSIOLOGICAL ROLES OF POLYAMINES:

(1) DNA binding and protein synthesis

(2) Mediation of cell growth/cell death

(3) Hypusine synthesis (which is essential for cell survival/proliferation)

(4) Development and differentiation of the central nervous system

(5) Inward rectification of potassium channels
 

"Alright everyone. Just wanted to post up some information as i know a lot of you have been using agmatine for nutrient partioning, and pumps ect. This thread is not meant to deter anyone, nor say its a good or bad product. Im a Science guy, i read all the time and when i come across interesting articles, i tend to share them and love hearing feedback and discussion. This is how we all learn.

I specifically messaged coop about this because he is highly respectable, and has great knowledge. Im hoping this can lead to civil discussion where people can take what they want from it.

Agmatine study in rats

Essentially this study had a few groups with agmatine and rats were givin IP shots of the Agmatine. They recorded food intake and Alpha2 activity.

The study showed that in HIGHER doses, NPY/AgRP levels (hunger signals, carb cravings) were higher. They showed increased appetite and an orexigenic effect. The Amount of food was then tested when agmatine was given with yohimne and still showed an increase yet, Yohimbine attenuated npy plus agmatine stimulated feeding by 30%


"based on these findings, Agmatine reduces noradrenaline activity in the PVN via pre synaptic a2- adrenoreceptors, which in turn may promote the release of NPY and consequently stimulate eating"

Theres a lot more in the study, but these were in RATS, and they were injkections. But ive seen people taking up to 2g per day.

i think this is a good reading especially with summer coming up.... Pump is nice, but when it can come at the expense of an increased food intake and agonism of alpha 2s id be worried.

This can go hand in hand with what dan duchain said in Bodyopus.... Low calorie dieting can increase alpha 2 receptors. Increases in NPY and AgRP can influence Alpha-2 adrenos, and slow metabolism... This can be shown by rT3 levels.

increased NPY/AgRP with depressed leptin, increases alpha 2 agonism, and increased food intake can be a cause for disaster in some people

When N{PY/AgRP are raised there becomes issues with thyroid...

Theres definitely other mechanisms in here. but i just put down some kind of messy to post this thread."

_________________________

You forgot the effects it has on the NMDA (antagonist) and on the adreno receptors (On one hand it can be a partial agonist which may increase fat loss or it could be partial antagonist which would halt fat loss)

Recently this has been the latest craze on the forums. It is sort of the flavor of the month so to speak. It is mainly marketed as something to induce "teh pumps!" but from the looks of it to me, it comes with a couple negatives.

Agmatine: Biological Role and Therapeutic Potentials in Morphine Analgesia and Dependence

Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, α2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.
FT - https://www.aapsj.org/view.asp?art=aapsj080356

Agmatine recognizes alpha 2-adrenoceptor binding sites but neither activates nor inhibits alpha 2-adrenoceptors.

It has been suggested that agmatine (decarboxylated arginine) is an endogenous clonidine-displacing substance (CDS) which recognizes 2-adrenoceptor and non-adrenoceptor, imidazoline binding sites. We have examined the effect of agmatine at 2-adrenoceptor binding sites and pre- and postjunctional 2-adrenoceptors. Agmatine produced a concentration-dependent inhibition of 1 nmol/l 3H-clonidine binding to both rat (pKi–5.10+-0.05) and bovine (pKi–4.77+-0.38) cerebral cortex membranes. However, agmatine (0.1–100 M) failed to activate pre-junctional 2-adrenoceptors regulating transmitter release in the guinea-pig isolated ileum and rat isolated vas deferens, nor did it activate post-junctional 2-adrenoceptors of the porcine isolated palmar lateral vein which mediate contraction or inhibition of forskolin-stimulated cyclic AMP formation. High concentrations of agmatine (10–30-fold the pKi at 2-adrenoceptor binding sites) failed to influence 2-adrenoceptor activation by either clonidine or UK-14304 (5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate) in any of the peripheral preparations examined. Moreover, even in a preparation where an interaction with 2-adrenoceptor binding sites on cell membranes can be demonstrated, the rat cerebral cortex, agmatine failed to inhibit forskolin-stimulated cyclic AMP in the intact tissue or affect the inhibition produced by the selective 2-adrenoceptor agonist UK-14304. Agmatine was also devoid of agonist activity in two preparations, the rat isolated thoracic aorta and the rat isolated gastric fundus, in which CDS has been reported to produce non-adrenoceptor effects. Thus, we have confirmed that agmatine recognizes 2-adrenoceptor binding sites and, therefore, is a CDS. However, since agmatine is devoid of pharmacological activity at either peripheral or central 2-adrenoceptors it can not account for earlier reports suggesting that brain-derived CDS can activate 2-adrenoceptors.
Cardiovascular responses to agmatine, a clonidine-displacing substance, in anesthetized rat.

We investigated the cardiovascular responses in anesthetized ventilated rats to agmatine (decarboxylated arginine), an amine which is an endogenous clonidine-displacing substance (CDS) synthesized in brain. Intracisternal agmatine dose-dependently increased sympathetic nerve activity and arterial pressure (at 400 nmol by 8.7 +/- 2.1 microV and 28.6 +/- 2.7 mmHg, respectively) and blocked arterial baroreflex reflexes. Microinjection of agmatine into the rostral ventrolateral medulla (RVL) had no effect on arterial pressure or sympathetic nerve activity while iontophoresis of agmatine onto defined vasomotor neurons of RVL was also without effect. Agmatine (i.v.) decreased sympathetic nerve activity and arterial pressure probably by blocking the transmission through sympathetic ganglia and by direct dilation of vascular smooth muscles. Despite binding like clonidine to alpha 2-adrenergic receptors and imidazoline (I)-receptors of both classes, agmatine does not replicate the central or peripheral actions of clonidine. The results suggest that earlier cardiovascular actions of partially purified CDS were either attributable to contaminating molecules and/or that CDS may be a family of molecules.
Cardiovascular effects of agmatine, a "clonidine-displacing substance", in conscious rabbits.

Agmatine has been identified as a "clonidine-displacing substance" in extracts from bovine brain. We studied its effect on cardiovascular regulation and the role played in this effect by alpha 2-adrenoceptors. In conscious rabbits, agmatine 10 micrograms kg-1 injected intracisternally (i.c.) caused no change, whereas agmatine 30, 100 and 300 micrograms kg-1 i.c. increased renal sympathetic nerve firing, the plasma concentration of noradrenaline and adrenaline and arterial blood pressure. Heart rate tended to be decreased. Yohimbine 1.5 micrograms kg-1 i.c. caused no change, whereas yohimbine 5, 15 and 50 micrograms kg-1 increased renal sympathetic nerve activity, the plasma concentration of noradrenaline and adrenaline, blood pressure and heart rate. In rabbit brain cortex slices preincubated with [3H]-noradrenaline, agmatine 1 to 100 microM did not modify the electrically evoked overflow of tritium (either 4 pulses at 100 Hz or 36 pulses at 3 Hz). The evoked overflow was reduced by 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304) 0.03 to 30 nM (4 pulses at 100 Hz), and this inhibition was not affected by agmatine 10 and 100 microM. Agmatine did not change the basal efflux of tritium. The results show that agmatine, like yohimbine, causes central sympathoexcitation when given i.c., but agmatine differs from yohimbine in that it does not increase heart rate. Agmatine acts neither as an agonist nor as an antagonist at the alpha 2-autoreceptors in rabbit brain cortex. alpha 2-Adrenoceptors, therefore, are probably not involved in its cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Agmatine: an endogenous clonidine-displacing substance in the brain.

Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.
So it is an antagonist for NDMA receptor and agonist for the alpha 2

Agmatine, an endogenous modulator of noradrenergic neurotransmission in the rat tail artery.

1. We investigated the vascular effects of agmatine (decarboxylated arginine), an endogenous ligand for alpha 2-adrenoceptors and non-adrenoceptor imidazoline (I-) receptors, present in endothelium, smooth muscle and plasma, using the rat tail artery as a model. 2. While by itself agmatine (10 nM-1 mM) was without effect on isolated arterial rings, at the highest concentration used (1 mM) it slightly increased EC50 values for contractions elicited respectively by the alpha 1- and alpha 2- adrenoceptor agonists methoxamine and clonidine. 3. Agmatine (0.03-1 mM) produced a concentration-dependent transient inhibition of the contractions induced by transmural nerve stimulation (TNS; 200 mA, 0.2 ms, 1 Hz, 10 s). This effect was abolished by the alpha 2-adrenoceptor antagonists, rawolscine and idazoxan. 4. In the presence of rawolscine or idazoxan, agmatine produced a concentration-dependent delayed facilitation of TNS-induced contractions, which was prevented by cocaine. 5. Neither inhibitory nor potentiating actions were produced by agmatine on contractions induced by noradrenaline (NA) administration. 6. Agmatine did not directly affect [3H]-NA uptake in bovine cultured chromaffin cells. 7. Agmatine can regulate vascular function by two opposing actions at sympathetic nerve terminals, with different latencies: a transient inhibition of NA release mediated by prejunctional alpha 2-adrenoceptors and a cocaine-sensitive delayed facilitation the mechanism of which is undetermined at present. 8. The results reveal the existence of a novel endogenous amine modulating NA release in the perivascular sympathetic terminals.
And also looks like agmatine can inhibit NA release (agonizes Aplha 2)

Combine these with its potential to increase hunger hormones NPY/AgRP and you have the reasons why I dont mess with it.

You should not administer B6 with L-Dopa if you want L-Dopa to take on its full effects.

L-Dopa converts to Dopamine. Dopamine cannot cross the blood brain barrier. If you arent increasing brain dopamine levels, how are you doing anything for hormone release?

So, you want the conversion of L-Dopa to Dopamine to occur in the brain, NOT outside of the brain. When you combine B6 with L-Dopa it does in fact enhance this conversion, but it makes more of it happen OUTSIDE of the brain, not inside. So B6 makes L-Dopa less effective for bodybuilding purposes.

Inhibition of l-Dopa-Induced Growth Hormone Stimulation by Pyridoxine and Chlorpromazine

Abstract

One gram of l-dopa was administered orally to 12 male control subjects and induced an increase of growth hormone (GH) secretion. The l-dopa-induced GH response was inhibited by an intravenous infusion of pyridoxine, but pyridoxine did not inhibit the GH response to hypoglycemia. Chlorpromazine also inhibited l-dopa-induced GH stimulation. Glucose concentrations were unaffected by l-dopa, chlorpromazine, and pyridoxine administration in these subjects. The mechanism of the suppressed l-dopa-induced GH response by pyridoxine appears to be mediated by peripheral acceleration of the conversion of l-dopa to dopamine, while that of chlorpromazine appears to be mediated through hypothalamic centers. Pyridoxine and chlorpromazine should be added to the list of other factors affecting the response to L-dopa-induced GH stimulation.




Failure of vitamin B6 to reverse the l-dopa effect in patients on a dopa decarboxylase inhibitor

Abstract

Seven patients with Parkinsonism previously on l-dopa were placed on a regimen of l-dopa and alpha methyl dopa hydrazine (a dopa decarboxylase inhibitor). Two of these patients had previously shown marked clinical deterioration of the l-dopa improvement when given pyridoxine. None of the seven patients receiving alpha methyl dopa hydrazine demonstrated any change in their condition when given pyridoxine. The failure of vitamin B6 to reverse the clinical effect of l-dopa in patients receiving both l-dopa and a peripheral dopa decarboxylase inhibitor suggests that reversal of the l-dopa effect induced by vitamin B6 is due to increasing the activity of the enzyme dopa decarboxylase outside the central nervous system.




ON THE MECHANISM OF THE NULLIFICATION OF CNS EFFECTS OF l-DOPA BY PYRIDOXINE IN PARKINSONIAN PATIENTS


Abstract

Administration of either Levodopa (l-DOPA) or pyridoxine increased the concentration of dopamine in the basal ganglia of rats. However, administration of pyridoxine to rats pretreated with l-DOPA for several days resulted in a reversal of the l-DOPA-induced elevation of dopamine. Pretreatment of rats with Ro 4-4602 (an inhibitor of peripheral aromatic amino acid decarboxylases) enhanced the l-DOPA-induced rise in the CNS level of dopamine. This effect was also reduced substantially after the administration of pyridoxine. We interpret these results to indicate that the antagonistic effect of pyridoxine on the beneficial effects of l-DOPA in the CNS is centrally mediated as a result of decreased formation of dopamine.

Now you're asking: If P5P crosses blood brain barrier and so does L-Dopa shouldn't it enhance dopamine formation on both sides?

Yes, but, it also increases Dopamine conversion OUTSIDE the BBB by a much larger amount (more blood outside the brain than inside) so the net effect is negative. That's why you want an L-Dopa source that includes a decarboxylase inhibitor. Bulk 1-Carboxy from USP has that, and is a much more concentrated source of L-Dopa than just straight Mucuna. Decarboxylase inhibitors prevent excess conversion within the body.

Introduction
Piracetam is a derivative of GABA which was originally designed to be an anxiolytic. Later testing revealed that it had no sedative or GABAergic effects, however it demonstrated an ability to enhance learning and cognition in some animal models. Further studies revealed a global cerebroprotective effect in the context of dementia, hypoxia, and other brain impairments.

In addition to its lack of GABAergic activity, it also lacks dopaminergic, anticholinergic, and antihistaminergic activity. Its one notable receptor interaction includes glutaminergic modulation at the NMDA and AMPA receptors.

Pharmacodynamics
Piracetam's ability to positively modulate the glutamate NMDA channel has been known for decades, however its ability to interact with the AMPA receptor is a fairly new discovery (1). Although piracetam binds to the AMPA receptor with a much lower affinity than the ampakines or aniracetam, it can bind to multiple sites on the AMPA receptor and may potentiate the effects of these agents acting on the AMPA receptor. Similarly, positively modulating the AMPA receptor itself increases the activation of the NMDA receptor, and so piracetam can be considered to be somewhat self-potentiating.

CNS Activity
Although piracetam does not directly activate any receptor, it positively modulates certain CNS glutaminergic receptors through allosteric activation. Allosterism is a dynamic method of facilitating receptor activation by binding to a receptor subunit that is distant from the agonist binding site. One of the advantages of allosteric activation is that it supports receptor activation even in the presence of physiological receptor antagonists (barbiturates, benzodiazepines, alcohol). Similarly, allosterism prevents receptor over-activation in the presence of excessive agonist (glutamate). The latter characteristic is one of the modalities by which piracetam helps to prevent brain excitotoxicity in the context of hypoxia or traumatic brain injuries.

The NMDA receptor is a voltage-dependent ion channel that allows calcium to enter the neuron along its concentration gradient after activation by glutamate and glycine (or D-serine). Normally, this channel is blocked by a positively charged magnesium ion which is attracted to the negatively charged intracellular compartment. In order for the magnesium ion to be displaced, the intracellular environment must possess a net positive charge.



This circumstance is made possible when glutamate first activates the AMPA channel. These channels then allow the rapid influx of positively charged sodium ions which results in a temporary reversal of polarity of the intracellular compartment.



After influx through the NMDA channel, ionic calcium is able to activate various enzymes including those that increase the transcription of various genes.

The Theory
The NMDA receptor is intricately linked to memory encoding and storage. As mentioned above, activating the receptor causes the transcription of products responsible for neuronal plasticity, growth, and survival. These include the growth hormone Brain Derived Neurotrophic Factor (BDNF) and its receptor trkB (4, 5, 6, 7). Increasing BDNF is one of the mechanisms by which antidepressants reverse depression. Similarly, agents which potentiate the NMDA receptor (via potentiating the AMPA receptor) have demonstrated cognitive enhancing abilities in normal non-human primates, as well as the ability to completely reverse sleep deprivation (8, 9). Conversely, NMDA antagonists like ketamine and phenylcyclidine are well known to disrupt cognition, and impair memory formation.

In addition to enhancing glutaminergic neurotransmission, piracetam also effects, and is effected by, the cholinergic system. This system consists of 2 families of receptors (metabotropic & ionotropic) and its ligand, acetylcholine (Ach). In dementia and cognitive decline, both types of receptors are diminished along with the production of acetylcholine. The reason for the latter is due to a generalized death of acetylcholine producing neurons in the hippocampus, and due to diminished production of the enzyme choline acetyl transferase. The latter is responsible for the reason that supplementing with acetylcholine precursors has little impact on cognition in dementia, whereas compounds that prevent the degredation of acetylcholine (Acetylcholinesterase Inhibitors) markedly improve dementia symptoms.

One of the reasons why acetylcholine is able to improve cognition and memory is due to its effects on the NMDA receptor. Specifically, agonizing the M1 acetylcholine receptor enhances the responsiveness to NMDA stimulation by causing the pre-synaptic release of glutamate (10). Similarly, agonism of nicotinic Ach (nAch) receptors on post-synaptic neurons synergizes with the AMPA receptor in reversing the polarity of the intracellular environment, thereby encouraging NMDA activation (11). The densities of both types of receptors are diminished in dementia and mild-cognitive decline. In rats, piracetam has demonstrated the ability of restoring metabotropic Ach receptors in the frontal cortex of aged rats, along with facilitating the release of acetylcholine in the hippocampus (2). In another rat experiment, combining choline and piracetam together resulted in a profound enhancement of memory formation versus either compound used alone (13).


The Reality
Unfortunately, piracetam has never demonstrated a clear benefit in healthy humans. Even in mice studies, young healthy animals are generally immune to the effects of piracetam (2). The reason for this dichotomy is due to piracetams low potency at the NMDA receptor, and even lower potency at the AMPA receptor. Since the NMDA receptor is reliant upon the AMPA receptor for activation, piracetam is pharmacodynamically challenged.

As recent studies have demonstrated, the main modality by which piracetam is now thought to enact its cerebroprotective effect is by enhancing the fluidity of the lipid bilayer; specifically, the fluidity of the mitochondrial membrane (3). The exact mechanism for this characteristic is unknown, although we do know that piracetam possesses no radical scavenging properties.

In the aged brain, complexes I and IV of the electron transport chain (ETC) become less active and result in the unchecked production of reactive oxygen species (ROS) which ends up damaging the DNA and cell membrane. Piracetam has been shown to increase the activity of both complexes and it has been suggested that this characteristic may support mitochondrial longevity.

In addition to supporting the energetic needs of the neuron, the mitochondria also regulates intracellular calcium and prevents it from activating deleterious enzymes and cascades. As discussed above, piracetam is an allosteric regulator of the NMDA channel and prevents excessive calcium influx. Similarly, by restoring the fluidity of the mitochondrial membrane, piracetam enhances the mitochondrial's ability to sequestor calcium.

The vast majority of healthy adults who use piracetam have sufficient mitochondrial membrane fluidity, and therefore piracetam's ability to enhance cognition through this mechanism is muted.
 

Enhancing the Effects of Piracetam
Piracetam has multiple known mechanisms for encouraging memory formation and cognition. Unfortunately, most of the effects are only observed in the context of abnormal brain function. Luckily, due to recent studies which have more comprehensively examined the mechanisms behind piracetam, it is possible to increase the effects of piracetam through synergisms.

As noted above, piracetam has been shown to increase the activity of Complexes I and IV of the ETC. Piracetam has also been shown to support mitochondrial longevity and function by enhancing membrane fluidity.




Coenzyme Q10 (CoQ10) is a fat soluble compound which participates in the ETC as an electron acceptor from Complex I and II. Relative deficiencies of CoQ10 have generalized deleterious effects on the body, mostly as a result of mitochondrial dysfunction. Supplemental CoQ10 has a multitude of health benefits including limiting membrane peroxidation, and reducing ROS formation. The latter two mechanisms would naturally support mitochondrial longevity and function, and synergize well with piracetam. Co-supplementing with Vitamin E helps to regenerate the active form of CoQ10, ubiquinol from its oxidized form, ubiquinone. There is also some evidence that the combination increases tissue retention of CoQ10 (14). Keep in mind that these effects would require chronic supplementation in order to be observed, and that the effects will be much more pronounced in those experiencing progressive memory decline.

The next mechanism by which piracetam may enhance cognition is by supporting cholinergic neurotransmission. Studies have shown that piracetam increases the density of metabotropic acetylcholine receptors in the cerebral cortex, and that it facilitates neuronal acetylcholine release in the hippocampus. The former mechanism may support attention and working memory through norepinephrine release and the latter may support cognition by downstream mechanisms involving the NMDA receptor. Acetyl-L-Carnitine (ALCAR) has been shown to increase the production of metabotropic glutamate receptors in various parts of the brain, although not in the hippocampus. The significance of this effect is unclear, especially in relation to cognition. One of the biggest mechanisms by which ALCAR may synergize with piracetam is by enhancing the production of acetylcholine by amplifying the enzyme choline acetyl transferase (15).




As mentioned above, the aged and demented brain has a diminished production of choline acetyl transferase. This enzyme is responsible for converting acetylcholine precursors into acetylcholine. Without an ability to maintain an acetylcholine reserve, Ach receptors slowly down-regulate resulting in self-perpetuating cognitive deterioration. Futhermore, since Ach receptors are intimately linked to the glutaminergic system, a decrement in Ach or Ach receptors will result in diminished BDNF production, thereby removing the signal for neuronal growth and survival.



Summary
Piracetam is the grandfather of nootropics and has been studied for the last 50 years. The effects of piracetam are subtle, even in the context of brain pathology. There is some evidence that its beneficial effects may accumulate over longer periods of time. The dosage of piracetam required to meet the minimum threshold for physiological significance is 5 grams per day. In order to maximize the effects of piracetam, the addition of CoQ10, Vitamin E, and ALCAR, should warrant contemplation. Similarly, supplementing with a choline source (Lecithin, CDP-Choline, Alpha-GPC) is a logical assumption based on the mechanisms proposed above, in addition to the rat study which demonstrated synergism. Utilizing an acetylcholine esterase inhibitor (AchEi) is a more advanced protocol and will be discussed in the next article.


References
(1) https://www.ncbi.nlm.nih.gov/pmc/arti...7/?tool=pubmed
(2) https://www.springerlink.com/content/r2n324624xt644j7/
(3) https://www.ncbi.nlm.nih.gov/pubmed/9037245
(4) https://www.ncbi.nlm.nih.gov/pubmed/20095391
(5) https://www.sciencedirect.com/science...80450469008299
(6) https://www.ncbi.nlm.nih.gov/pmc/arti...6/?tool=pubmed
(7) https://www.ncbi.nlm.nih.gov/pubmed/12663749
(8) https://www.ncbi.nlm.nih.gov/pubmed/16104830
(9) https://www.ncbi.nlm.nih.gov/pubmed/22054117
(10) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33643/
(11) https://jpet.aspetjournals.org/content/280/3/1117.short
(12) https://www.sciencedirect.com/science...91305784902168
(13) https://www.sciencedirect.com/science...97458081900075
(14) https://jn.nutrition.org/content/130/9/2343.short
(15) https://www.ncbi.nlm.nih.gov/pubmed/7563233
(16) https://www.ncbi.nlm.nih.gov/pmc/arti...6/?tool=pubmed

-Higher Tower Pharmcology

Just wanted to dedicate a thread to any companies incorporating this PEAK-ATP/oral nucleotide garbage into their formulas. Maybe your general consumer base is completely unaware however, this practice is akin to using sand as a filler, and it's time to be exposed. Side Effect Sports is by far the worst offender with the primary bulk of their products being worthless nucleotides that are rapidly & extensively annihilated via luminal & hepatic-dephosphorylation/degradation following oral administration. I confronted the owner of SES but to no avail. He simply refused to acknowledge the pharmacokinetic-conundrum that they've gotten themselves into. I have a feeling the SES reps have even been instructed to not venture outside of the company promo section in fear of exposure. If you plan on using any of these supplements in the future.... be sure to get the IV bag ready.

So in addition to Side Effect Sports entire lineup consisting of this flavored sand: Pre-Workout/Post Workout/Muscle Builder/Fat Burner/Energy/Endurance

MassPro Sythagen, Gaspari SuperPump Max, BSN Hyper FX/Epozine-O2, MRM Driven, Inner Armour Power Peak, are also guilty:

[]

Br J Nutr. 2011 Feb;105(3):357-66. Epub 2010 Dec 6.
Coolen EJ, Arts IC, Bekers O, Vervaet C, Bast A, Dagnelie PC.
Oral bioavailability of ATP after prolonged administration.

Purinergic receptors are important for the regulation of inflammation, muscle contraction, neurotransmission and nociception. Extracellular ATP and its metabolites are the main ligands for these receptors. Occasional reports on beneficial results of ATP administration in human and animal studies have suggested the bioavailability of oral ATP supplements. We investigated whether prolonged daily intake of oral ATP is indeed bioavailable. Thirty-two healthy subjects were randomised to receive 0, 250, 1250 or 5000 mg ATP per d for 28 d by means of enteric-coated pellets. In addition, on days 0 and 28, all thirty-two subjects received 5000 mg ATP to determine whether prolonged administration would induce adaptations in the bioavailability of ATP. ATP supplementation for 4 weeks did not lead to changes in blood or plasma ATP concentrations. Of all ATP metabolites, only plasma uric acid levels increased significantly after the administration of 5000 mg of ATP. Prolonged administration of ATP was safe as evidenced from liver and kidney parameters. We conclude that oral administration of ATP only resulted in increased uric acid concentrations. On the basis of these findings, we seriously question the claimed efficacy of oral ATP at dosages even lower than that used in the present study.



J Int Soc Sports Nutr. 2012 Apr 17;9(1):16. [Epub ahead of print]
Arts IC, Coolen EJ, Bours MJ, Huyghebaert N, Cohen Stuart MA, Bast A, Dagnelie PC.
Adenosine 5' -triphosphate (ATP) supplements are not orally bioavailable: a randomized, placebocontrolled cross-over trial in healthy humans.

BACKGROUND:

Nutritional supplements designed to increase adenosine 5' -triphosphate (ATP) concentrations are commonly used by athletes as ergogenic aids. ATP is the primary source of energy for the cells, and supplementation may enhance the ability to maintain high ATP turnover during high-intensity exercise. Oral ATP supplements have beneficial effects in some but not all studies examining physical performance. One of the remaining questions is whether orally administered ATP is bioavailable. We investigated whether acute supplementation with oral ATP administered as enteric-coated pellets led to increased concentrations of ATP or its metabolites in the circulation.

METHODS:

Eight healthy volunteers participated in a cross-over study. Participants were given in random order single doses of 5000 mg ATP or placebo. To prevent degradation of ATP in the acidic environment of the stomach, the supplement was administered via two types of pH-sensitive, enteric-coated pellets (targeted at release in the proximal or distal small intestine), or via a naso-duodenal tube. Blood ATP and metabolite concentrations were monitored by HPLC for 4.5 h (naso-duodenal tube) or 7 h (pellets) post-administration. Areas under the concentration vs. time curve were calculated and compared by paired-samples t-tests.

RESULTS:

ATP concentrations in blood did not increase after ATP supplementation via enteric-coated pellets or naso-duodenal tube. In contrast, concentrations of the final catabolic product of ATP, uric acid, were significantly increased compared to placebo by ~50% after administration via proximal-release pellets (P = 0.003) and naso-duodenal tube (P = 0.001), but not after administration via distal-release pellets.

CONCLUSIONS:

A single dose of orally administered ATP is not bioavailable, and this may explain why several studies did not find ergogenic effects of oral ATP supplementation. On the other hand, increases in uric acid after release of ATP in the proximal part of the small intestine suggest that ATP or one of its metabolites is absorbed and metabolized. Uric acid itself may have ergogenic effects, but this needs further study. Also, more studies are needed to determine whether chronic administration of ATP will enhance its oral bioavailability.

-NoHype